Muskarinski acetilholinski receptor M₄

Muskarinski acetilholinski receptor M4
Identifikatori
Simboli	CHRM4; HM4; M4R
Vanjski ID	OMIM: 118495 MGI: 88399 HomoloGene: 20192 IUPHAR: M4 GeneCards: CHRM4 Gene
Ontologija gena
Molekularna funkcija	• receptorska aktivnost; • aktivnost G-protein spregnutog receptora; • aktivnost muskarinskog acetilholinskog receptora; • aktivnost faktor razmene guanil-nukleotida;
Celularna komponenta	• membranska frakcija; • ćelijska membrana; • integralno sa ćelijskom membranom; • postsinaptička gustina; • ćelijska spoj; • asimetrična sinapsa; • sarkolema; • neuronsko ćelijsko telo; • aksonski terminus; • intracelularni deo; • postsinaptička membrana;
Biološki proces	• prenos signala; • signalni put receptora sa ćelijske površine; • inhibicija aktivnosti adenilat ciklaze muskarinskim acetilholinskim receptorima; • signalni put muskarinskog acetilholinskog receptora; • ćelijska proliferacija; • respons na organske supstance;
Ortolozi

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Muskarinski acetilholinski receptor M₄ (muskarinski holinergijski receptor 4, CHRM4), je protein koji je kod ljudi kodiran CHRM4 genom.^[1]^[2]

Funkcije

Muskarinski acetilholinski receptori pripadaju velikoj familiji G protein spregnutih receptora. Funkcionalna raznovrsnost ovih receptora je definisana vezivanjem acetilholina, i obuhvata ćelijske odgovore poput inhibicije adenilat ciklaze, fosfoinozitidne degeneracije i modulacije kalijumovih kanala. Muskarinski receptori posreduju mnoge efekte acetilholina u centralnom i perifernom nervnom sistemu. Klinički značaj ovoj receptora nije poznat; međutim, studije na miševima su ustanovile vezu između njegovog dejstva i inhibicije adenilil ciklaze.^[1]

M₄ muskarinski receptori deluju kao inhibitorni autoreceptori za acetilholin. Aktivacija M₄ receptora inhibira oslobađanje acetilholina u striatumu. M₂ podtip acetilholinksog receptora deluje na sličan način, kao inhibitorni autoreceptor acetilholinskog otpuštanja, mada taj receptor deluje prvenstveno u hipokampusu i cerebralnom korteksu.

Muskarinski acetilholinski receptori imaju regulatorno dejstvo na dopaminergijsku neurotransmisiju. Aktivacija M₄ receptora u striatumu inhibira D₁-indukovanu lokomotornu stimulaciju kod miševa. Miševi koji su deficitarni u M₄ receptorima ispoljavaju povećanu lokomotornu stimulaciju u odgovoru na D₁ agoniste, amfetamin i kokain.^[3]^[4]^[5] Neurotransmisija u striatumu utiče na ekstrapiramidalnu motornu kontrolu, tako da alteracije M₄ aktivnosti mogu da doprinosu oboljenjima poput Parkinsonove bolesti.^[6]^[7]^[8]

Ligandi

Ortosterni agonisti

Alosterni agonisti

LY-2033298 ^[9]
VU-0152100
VU-0152099 ^[10]

Antagonisti

AFDX-384 (mešoviti M2/M4 antagonist, N-[2-[2-[(dipropilamino)metil]-1-piperidinil]etil]-5,6-dihidro-6-okso-11H-pirido[2,3-b][1,4]benzodiazepin-11-karboksamid
Dicikloverin^[11]
Himbacin
Mamba toksin 3^[12]
PD-102,807 etil estar (3,6a,11,14-tetrahidro-9-metoksi-2-metil-(12H)-izohino[1,2-b]pirolo[3,2-f][1,3]benzoksazin-1-karboksilne kiseline
PD-0298029
Tropikamid - umereno selektivan u odnosu na druge muskarinske podtipove (oko 2-5 puta)^[13]

Reference

↑ ^1,0 ^1,1 „Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4”.
↑ Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (May 1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)”. Genomics 13 (1): 239–40. DOI:10.1016/0888-7543(92)90236-L. PMID 1577490.
↑ Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (August 1999). „Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice”. Proceedings of the National Academy of Sciences of the United States of America 96 (18): 10483–8. PMC 17915. PMID 10468635.
↑ Jeon J, Dencker D, Wörtwein G, et al. (February 2010). „A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors”. J. Neurosci. 30 (6): 2396–405. DOI:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442. PMID 20147565.
↑ Schmidt L. S., Thomsen M., Weikop P., Dencker D., Wess J. R., Woldbye D. P. D., Wortwein G., Fink-Jensen A. (2011). „Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice”. Psychopharmacology 216 (3): 367–378. DOI:10.1007/s00213-011-2225-4. PMID 21373792.
↑ Langmead CJ, Watson J, Reavill C (February 2008). „Muscarinic acetylcholine receptors as CNS drug targets”. Pharmacology & Therapeutics 117 (2): 232–43. DOI:10.1016/j.pharmthera.2007.09.009. PMID 18082893.
↑ Stein IS, Hell JW (June 2010). „CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion”. The EMBO Journal 29 (12): 1943–5. DOI:10.1038/emboj.2010.105. PMC 2892364. PMID 20551968.
↑ Guo ML, Mao LM, Wang JQ (December 2010). „Modulation of M4 muscarinic acetylcholine receptors by interacting proteins”. Neuroscience Bulletin 26 (6): 469–73. PMC 3139403. PMID 21113197.
↑ Chan WY, McKinzie DL, Bose S, et al. (2008). „Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia”. PNAS 105 (31): 10978–83. DOI:10.1073/pnas.0800567105. PMC 2495016. PMID 18678919.
↑ Brady AE, Jones CK, Bridges TM, et al. (2008). „Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats”. J. Pharmacol. Exp. Ther. 327 (3): 941–53. DOI:10.1124/jpet.108.140350. PMC 2745822. PMID 18772318.
↑ Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (June 2005). „Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies”. Behavioural Brain Research 161 (2): 299–305. DOI:10.1016/j.bbr.2005.02.019. PMID 15922057.
↑ Muscarinic toxin 3, Dendroaspis angusticeps (Eastern green mamba)
↑ Lazareno S, Buckley NJ, Roberts FF (December 1990). „Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells”. Molecular Pharmacology 38 (6): 805–15. PMID 2250662.

Literatura

Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (1989). „Muscarinic receptor subtypes. Physiology and clinical implications.”. N. Engl. J. Med. 321 (15): 1022–9. DOI:10.1056/NEJM198910123211506. PMID 2674717.
Brann MR, Ellis J, Jørgensen H, et al. (1994). „Muscarinic acetylcholine receptor subtypes: localization and structure/function.”. Prog. Brain Res. 98: 121–7. DOI:10.1016/S0079-6123(08)62388-2. PMID 8248499.
Grewal RP, Martinez M, Hoehe M, et al. (1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4).”. Genomics 13 (1): 239–40. DOI:10.1016/0888-7543(92)90236-L. PMID 1577490.
Detera-Wadleigh SD, Wiesch D, Bonner TI (1989). „An SstI polymorphism for the human muscarinic acetylcholine receptor gene, m4 (CHRM 4).”. Nucleic Acids Res. 17 (15): 6431. DOI:10.1093/nar/17.15.6431. PMC 318330. PMID 2570410.
Ashkenazi A, Ramachandran J, Capon DJ (1989). „Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.”. Nature 340 (6229): 146–50. DOI:10.1038/340146a0. PMID 2739737.
Bonner TI, Buckley NJ, Young AC, Brann MR (1987). „Identification of a family of muscarinic acetylcholine receptor genes.”. Science 237 (4814): 527–32. DOI:10.1126/science.3037705. PMID 3037705.
Bonner TI, Young AC, Brann MR, Buckley NJ (1990). „Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.”. Neuron 1 (5): 403–10. DOI:10.1016/0896-6273(88)90190-0. PMID 3272174.
Peralta EG, Ashkenazi A, Winslow JW, et al. (1988). „Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.”. EMBO J. 6 (13): 3923–9. PMC 553870. PMID 3443095.
van Koppen CJ, Lenz W, Nathanson NM (1993). „Isolation, sequence and functional expression of the mouse m4 muscarinic acetylcholine receptor gene.”. Biochim. Biophys. Acta 1173 (3): 342–4. PMID 7916637.
Haga K, Kameyama K, Haga T, et al. (1996). „Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.”. J. Biol. Chem. 271 (5): 2776–82. DOI:10.1074/jbc.271.5.2776. PMID 8576254.
von der Kammer H, Mayhaus M, Albrecht C, et al. (1998). „Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.”. J. Biol. Chem. 273 (23): 14538–44. DOI:10.1074/jbc.273.23.14538. PMID 9603968.
Oldenhof J, Vickery R, Anafi M, et al. (1998). „SH3 binding domains in the dopamine D4 receptor.”. Biochemistry 37 (45): 15726–36. DOI:10.1021/bi981634. PMID 9843378.
Sato KZ, Fujii T, Watanabe Y, et al. (1999). „Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines.”. Neurosci. Lett. 266 (1): 17–20. DOI:10.1016/S0304-3940(99)00259-1. PMID 10336173.
Dias Neto E, Correa RG, Verjovski-Almeida S, et al. (2000). „Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.”. Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3491–6. DOI:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
Wang H, Han H, Zhang L, et al. (2001). „Expression of multiple subtypes of muscarinic receptors and cellular distribution in the human heart.”. Mol. Pharmacol. 59 (5): 1029–36. PMID 11306684.
Buchli R, Ndoye A, Arredondo J, et al. (2002). „Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes.”. Mol. Cell. Biochem. 228 (1–2): 57–72. DOI:10.1023/A:1013368509855. PMID 11855742.
McClatchy DB, Knudsen CR, Clark BF, et al. (2002). „Novel interaction between the M4 muscarinic acetylcholine receptor and elongation factor 1A2”. J. Biol. Chem. 277 (32): 29268–74. DOI:10.1074/jbc.M203081200. PMID 12048193.
Dean B, McLeod M, Keriakous D, et al. (2003). „Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia”. Mol. Psychiatry 7 (10): 1083–91. DOI:10.1038/sj.mp.4001199. PMID 12476323.

[entrez-1] 1,0 ^1,1 „Entrez Gene: CHRM4 cholinergic receptor, muscarinic 4”.

[pmid1577490-2] Grewal RP, Martinez M, Hoehe M, Bonner TI, Gershon ES, Detera-Wadleigh S (May 1992). „Genetic linkage mapping of the m4 human muscarinic receptor (CHRM4)”. Genomics 13 (1): 239–40. DOI:10.1016/0888-7543(92)90236-L. PMID 1577490.

[pmid10468635-3] Gomeza J, Zhang L, Kostenis E, Felder C, Bymaster F, Brodkin J, Shannon H, Xia B, Deng C, Wess J (August 1999). „Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice”. Proceedings of the National Academy of Sciences of the United States of America 96 (18): 10483–8. PMC 17915. PMID 10468635.

[pmid20147565-4] Jeon J, Dencker D, Wörtwein G, et al. (February 2010). „A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors”. J. Neurosci. 30 (6): 2396–405. DOI:10.1523/JNEUROSCI.3843-09.2010. PMC 2824442. PMID 20147565.

[5] Schmidt L. S., Thomsen M., Weikop P., Dencker D., Wess J. R., Woldbye D. P. D., Wortwein G., Fink-Jensen A. (2011). „Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice”. Psychopharmacology 216 (3): 367–378. DOI:10.1007/s00213-011-2225-4. PMID 21373792.

[pmid18082893-6] Langmead CJ, Watson J, Reavill C (February 2008). „Muscarinic acetylcholine receptors as CNS drug targets”. Pharmacology & Therapeutics 117 (2): 232–43. DOI:10.1016/j.pharmthera.2007.09.009. PMID 18082893.

[pmid20551968-7] Stein IS, Hell JW (June 2010). „CaMKII hunkers down on the muscarinic M4 receptor to help curb cocaine-induced hyperlocomotion”. The EMBO Journal 29 (12): 1943–5. DOI:10.1038/emboj.2010.105. PMC 2892364. PMID 20551968.

[pmid21113197-8] Guo ML, Mao LM, Wang JQ (December 2010). „Modulation of M4 muscarinic acetylcholine receptors by interacting proteins”. Neuroscience Bulletin 26 (6): 469–73. PMC 3139403. PMID 21113197.

[pmid18678919-9] Chan WY, McKinzie DL, Bose S, et al. (2008). „Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia”. PNAS 105 (31): 10978–83. DOI:10.1073/pnas.0800567105. PMC 2495016. PMID 18678919.

[pmid18772318-10] Brady AE, Jones CK, Bridges TM, et al. (2008). „Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats”. J. Pharmacol. Exp. Ther. 327 (3): 941–53. DOI:10.1124/jpet.108.140350. PMC 2745822. PMID 18772318.

[pmid15922057-11] Teaktong T, Piggott MA, Mckeith IG, Perry RH, Ballard CG, Perry EK (June 2005). „Muscarinic M2 and M4 receptors in anterior cingulate cortex: relation to neuropsychiatric symptoms in dementia with Lewy bodies”. Behavioural Brain Research 161 (2): 299–305. DOI:10.1016/j.bbr.2005.02.019. PMID 15922057.

[12] Muscarinic toxin 3, Dendroaspis angusticeps (Eastern green mamba)

[pmid2250662-13] Lazareno S, Buckley NJ, Roberts FF (December 1990). „Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells”. Molecular Pharmacology 38 (6): 805–15. PMID 2250662.

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Muskarinski acetilholinski receptor M4